This review evaluated the clinical validity and utility of DNA testing to detect hereditary haemochromatosis (HHC). The authors concluded that limited evidence suggested testing in at-risk populations had clinical validity and possible clinical utility. This was a largely well-conducted review and the authors conclusions were likely to be reliable.

Authors' objectives

To evaluate the clinical validity and utility of DNA testing to detect hereditary haemochromatosis (HHC).

Searching

Fifteen electronic databases were searched – including MEDLINE, the Cochrane Library, HuGENet (Human Genome Epidemiology Network) and Medion – to April 2007 to identify relevant studies for the review. Additional studies were sought from bibliographies of relevant publications and through contact with experts. For further details of the search strategy see Other Publications of Related Interest.

Study selection

For the assessment of clinical validity, studies of DNA tests conducted in northern European Caucasians with iron overload suggesting HHC compared to a control population were eligible for inclusion in the review. Studies had to report or allow for the calculation of sensitivity (the proportion of at-risk people who tested positively for C282Y homozygosity) and specificity (the probability of a negative test in people without the disease).

For the assessment of clinical utility, studies incorporating DNA tests conducted in the broader Caucasian population (including relatives of suspected cases) with iron overload suggesting HHC compared with cases identified without DNA testing were eligible for inclusion. Patient-based measures (for example, morbidity and mortality) were the utility outcomes of interest. There were no studies assessing clinical utility.

There was substantial variation within the included studies assessing clinical validity (for example, in terms of definitions of HHC and patient-relative status). The extent to which control groups were phenotypically negative or representative of the target population was unclear. Two independent reviewers selected the studies for inclusion. Differences were resolved through discussion.

Assessment of study quality

The quality of clinical validity studies was assessed using relevant criteria from the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tool, combined with other questions established to assess genetic testing. Two independent reviewers assessed the quality of studies; differences were resolved through discussion.

Data extraction

Data were extracted or calculated in order to report percentages for sensitivity and specificity. Two independent reviewers extracted the data; differences were resolved through discussion.

Methods of synthesis

A narrative synthesis was provided. Study differences were evident from the tabulated data. Sensitivity analyses were conducted to explore the effects of removing studies with an unclear definition of HCC; those where other causes of iron overload were excluded and where patients were unrelated; and a small study located in southern Europe.

Results of the review

Eleven observational studies with a control group assessing clinical validity were included in the review (n=3,637). Study quality was reported to be limited, with uncertainties recorded in terms of sampling methods and relationship status between patients.

Sensitivity ranged from 21.2 per cent to 100 per cent. When studies with clearly defined HHC were selected, sensitivity ranged from 72.2 per cent to 100 per cent. When the analysis was limited to studies that excluded other causes of iron overload and where patients were unrelated, the range was 72.2 per cent to 92.4 per cent (and was reported to be 91.3 per cent to 92.4 per cent when the southern European study was excluded). Specificity ranged from 98.8 per cent to 100 per cent.

Cost information

Results from two North American studies found that initial spousal genotyping was less costly than phenotypic testing of all participants (total cost in Canadian dollars of $35,600 compared with $58,200). Genotyping of siblings and children was less costly than serum iron testing. Compared with no screening, genotyping of children was associated with an incremental cost effectiveness ratio ranging from $508 to $3665 per life year saved, depending on number of children being tested.

Authors' conclusions

Limited evidence suggests that DNA testing for HHC in at-risk populations has clinical validity and may have clinical utility.

CRD commentary

The review addressed a clear question and was supported by adequately detailed inclusion criteria for aspects of study design, participants, interventions and outcomes. The search strategy appeared to include some relevant sources, including those relating to unpublished material. An appropriate quality assessment tool was reported to have been used, and the results of this were used to highlight the review findings. Adequate details of the included studies were provided, indicating the existence of substantial variation that necessitated a narrative synthesis of results. The review process was conducted with sufficient measures to minimise error and bias throughout. Overall, this was a largely well-conducted review and based on the evidence provided the authors' conclusions were likely to be reliable.

Implications of the review for practice and research

Practice: the authors stated that genetic testing was likely to be of value in clinical practice.

Research: the authors stated that prospective long-term follow up studies of DNA testing for HHC were needed.

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.